Study on mesothelioma diagnosis on cytologic preparations: Determination of neoplastic nature with p16 FISH and immunohistochemistry

• Project/Area Number: 16K08678
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Fukuoka University
• Principal Investigator: Nabeshima Kazuki 福岡大学, 医学部, 教授 (40189189)
• Co-Investigator(Kenkyū-buntansha): 濱崎 慎 福岡大学, 医学部, 准教授 (90412600)
• Research Collaborator: Matsumoto Shinji , 細胞検査士 ; Yano Kyoko , 技官 ; Hida Tomoyuki , 大学院生 ; Kamei Toshiaki PCL福岡病理・細胞診センター, 所長 ; Oda Yoshinao 九州大学, 教授 ; Maruyama Riruke 島根大, 教授 ; Sato Yuichiro 宮崎大, 准教授
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 中皮腫 / 細胞診 / FISH / 免疫組織化学 / 免疫細胞化学 / p16 / BAP1 / MTAP / mesothelioma / differential diagnosis / 9p21 / 胸膜中皮腫 / 欠失 / ホモ接合性欠失 / p16 FISH / p15

Outline of Final Research Achievements

In this study, we found that loss of expression of protein product of MTAP (methylthioadenosine phosphorylase) gene, located in the 9p21 region, correlated most with the deletion status of p16 gene as detected by FISH. This IHC detection of MTAP loss has been revealed to be useful for discriminating epithelioid mesothelioma from reactive mesothelial cell proliferations in tissues and cell blocks, with 100% specificity. MTAP IHC was also useful for distinguishing desmoplastic mesothelioma from fibrous pleuritis, with 100% specificity.

Academic Significance and Societal Importance of the Research Achievements

胸膜中皮腫は高悪性度腫瘍で、その発生は2035年頃まで増加すると予想されており、早期診断法の開発は喫緊の課題である。その腫瘍性はp16遺伝子のホモ欠失やBAP1遺伝子産物の消失によって確認できるが、前者はFISHによってのみ可能であった。しかし、今回の研究にて、MTAP遺伝子産物の免疫組織化学にて、p16遺伝子のホモ欠失を高率に予見できることが明らかとなったので、多くの医療機関にて、BAP1とMTAPの免染の組み合わせにて、中皮腫の診断が可能になった。FISHの代用としての免染手法の追求という学術的意義に加えて、日常診療への応用という社会的貢献は大きいと考えられる。

Research Products

• [Int'l Joint Research] University of Chicago(米国)
• [Int'l Joint Research] University of British Columbia(カナダ)
• [Journal Article] Highly expressed EZH2 in combination with BAP1 and MTAP loss, as detected by immunohistochemistry, is useful for differentiating malignant pleural mesothelioma from reactive mesothelial hyperplasia. (2019)
  • Author(s): Yoshimura M, Kinoshita Y, Hamasaki M, Matsumoto S, Hida T, Oda Y, Iwasaki A, Nabeshima K
  • Journal Title: Lung Cancer Volume: 130 Pages: 187-193
  • DOI: 10.1016/j.lungcan.2019.02.004
  • Peer Reviewed
• [Journal Article] A combination of MTAP and BAP1 immunohistochemistry is effective for distinguishing sarcomatoid mesothelioma from fibrous pleuritis (2018)
  • Author(s): Kinoshita Yoshiaki、Hamasaki Makoto、Yoshimura Masayo、Matsumoto Shinji、Sato Ayuko、Tsujimura Tohru、Ueda Hitoshi、Makihata Satoshi、Kato Fumiaki、Iwasaki Akinori、Nabeshima Kazuki
  • Journal Title: Lung Cancer Volume: 125 Pages: 198-204
  • DOI: 10.1016/j.lungcan.2018.09.019
  • Peer Reviewed
• [Journal Article] Pathologic separation of benign from malignant mesothelial proliferations and histologic/molecular analysis of malignant mesothelioma subtypes. (2018)
  • Author(s): Churg A, Nabeshima K, Ali G, Bruno R, Fernandez-Cuesta L, Galateau-Salle F
  • Journal Title: Lung Cancer Volume: 124 Pages: 95-101
  • DOI: 10.1016/j.lungcan.2018.07.041
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A combination of MTAP and BAP1 immunohistochemistry in pleural effusion cytology for the diagnosis of mesothelioma (2017)
  • Author(s): Kinoshita Yoshiaki、Hida Tomoyuki、Hamasaki Makoto、Matsumoto Shinji、Sato Ayuko、Tsujimura Tohru、Kawahara Kunimitsu、Hiroshima Kenzo、Oda Yoshinao、Nabeshima Kazuki
  • Journal Title: Cancer Cytopathology Volume: 126 Issue: 1 Pages: 54-63
  • DOI: 10.1002/cncy.21928
  • Peer Reviewed / Open Access
• [Journal Article] Immunohistochemical detection of MTAP and BAP1 protein loss for mesothelioma diagnosis: Comparison with 9p21 FISH and BAP1 immunohistochemistry. (2017)
  • Author(s): Hida T, Hamasaki M, Matsumoto S, Sato A, Tsujimura T, Kawahara K, Iwasaki A, Okamoto T, Oda Y, Honda H, Nabeshima K.
  • Journal Title: Lung Cancer Volume: 104 Pages: 98-105
  • DOI: 10.1016/j.lungcan.2016.12.017
  • Peer Reviewed
• [Journal Article] Usefulness of p16/CDKN2A fluorescence in situ hybridization and BAP1 immunohistochemistry for the diagnosis of biphasic mesothelioma. (2017)
  • Author(s): Wu D, Hiroshima K, Yusa T, Ozaki D, Koh E, Sekine Y, Matsumoto S, Nabeshima K, Sato A, Tsujimura T, Yamakawa H, Tada Y, Shimada H, Tagawa M.
  • Journal Title: Ann Diagn Pathol. Volume: 26 Pages: 31-37
  • DOI: 10.1016/j.anndiagpath.2016.10.010
  • Peer Reviewed
• [Journal Article] The differential diagnosis between pleural sarcomatoid mesothelioma and spindle cell/pleomorphic (sarcomatoid) carcinomas of the lung: evidence-based guidelines from the International Mesothelioma Panel and the MESOPATH National Reference Center. (2017)
  • Author(s): Marchevsky AM, LeStang N, Hiroshima K, Pelosi G, Attanoos R, Churg A, Chirieac L, Dacic S, Husain A, Khoor A, Klebe S, Lantuejoul S, Roggli V, Vignaud JM, Weynard B, Sauter J, Henderson D, Nabeshima K, Galateau-Salle F.
  • Journal Title: Hum Pathol Volume: 67 Pages: 160-168
  • DOI: 10.1016/j.humpath.2017.07.015
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Diagnostic application of BAP1 immunohistochemistry to differentiate pleural mesothelioma from metastatic pleural tumours. (2017)
  • Author(s): Yoshimura M, Kinoshita Y, Hamasaki M, Matsumoto S, Hida T, Oda Y, Nabeshima K.
  • Journal Title: Histopathology Volume: 71 Issue: 6 Pages: 1011-1014
  • DOI: 10.1111/his.13321
• [Journal Article] BAP1 immunohistochemistry and p16 FISH results in combination provide higher confidence in malignant pleural mesothelioma diagnosis: ROC analysis of the two tests. (2016)
  • Author(s): Hida T, Hamasaki M, Matsumoto S, Sato A, Tsujimura T, Kawahara K, Iwasaki A, Okamoto T, Oda Y, Honda H, Nabeshima K.
  • Journal Title: Pathol Int Volume: 66 Issue: 10 Pages: 563-570
  • DOI: 10.1111/pin.12453
  • Peer Reviewed
• [Presentation] Immunohistochemical detection of MTAP or BAP1 protein loss in tissues and cell blocks for diagnosis of mesothelioma. (2018)
  • Author(s): Nabeshima K, Kinoshita Y, Hamasaki M, Hida T, Matsumoto S, Sato A, Tsujimura T, Kawahara K, Hiroshima K, Iwasaki A, Oda Y
  • Organizer: 14th International Conference of the International Mesothelioma Interest Group
  • Int'l Joint Research
• [Presentation] 中皮腫の細胞像、組織像そして最近の話題（教育講演） (2018)
  • Author(s): 鍋島一樹、濵﨑慎、木下義晃、松本慎二、吉村雅代、樋田知之、佐藤鮎子、辻村亨、河原邦光、廣島健三、亀井敏昭、小田義直
  • Organizer: 第57回日本臨床細胞学会秋期大会
  • Invited
• [Presentation] Diagnosis of mesothelioma in tissues and cytological preparations: Update based on genetic abnormalities. (2018)
  • Author(s): Nabeshima K.
  • Organizer: The 25th Thai-Japanese Workshop in Diagnostic Cytopathology
  • Int'l Joint Research / Invited
• [Presentation] A combination of MTAP and BAP1 immunohistochemistry is effective for distinguishing sarcomatoid mesothelioma from fibrous pleuritic. (2018)
  • Author(s): Kinoshita Y, Hamasaki M, Yoshimura M, Matsumoto S, Sato A, Tsujimura T, Nabeshima K
  • Organizer: 107th Annual Meeting of United States & Canadian Academy of Pathology
  • Int'l Joint Research
• [Presentation] 肉腫型悪性胸膜中皮腫と線維性胸膜炎の鑑別におけるMTAP IHC及びBAP1 IHCの有用性 (2018)
  • Author(s): 木下 義晃、濱崎慎、吉村雅代、松本慎二、佐藤鮎子、辻村亨、鍋島一樹
  • Organizer: 第59回日本肺癌学会学術集会
• [Presentation] A combination of MTAP and BAP1 immunohistochemistry is useful for differentiating malignant and benign mesothelial proliferatons in tissue and cytological specimens. (2017)
  • Author(s): Yoshiaki Kinoshita, Tomoyuki Hida, Makoto Hamasaki1, Shinji Matsumoto1, Tohru Tsujimura, Kunimitsu Kawahara, Kenzo Hiroshima, Yoshinao Oda, and Kazuki Nabeshima.
  • Organizer: 106th Annual Meeting of United States & Canadian Academy of Pathology
  • Place of Presentation: San Antonio, Texas, USA
  • Year and Date: 2017-03-04
  • Int'l Joint Research
• [Presentation] Nuclear Grade, Necrosis and Solid Growth Pattern Predict Survival in Epithelioid Malignant Mesothelioma: An International, Multi-Institutional Study. (2017)
  • Author(s): Lauren E Rosen, Vijayalakshmi Ananthanarayanan, Alexander Gallan, Melissa Yuwono Tjota, Richard Attanoos, Fouad Alchami, Luka Brcic, Kelly Butnor, Kenzo Hiroshima, Astero Klampatsa, Leslie Litzky, Alberto M. Marchevsky, Filomena Medeiros, Angeles Montero, David Moore, Kazuki Nabeshima et al.
  • Organizer: 106th Annual Meeting of United States & Canadian Academy of Pathology
  • Int'l Joint Research
• [Presentation] BAP1 immunohistochemistry differentiates pleural mesothelioma not only from reactive mesothelial hyperplasia but also from metastatic pleural tumors. (2017)
  • Author(s): Masayo Yoshimura, Yoshiaki Kinoshita, Makoto Hamasaki, Shinji Matsumoto, Tomoyuki Hida, Yoshinao Oda, and Kazuki Nabeshima.
  • Organizer: 106th Annual Meeting of United States & Canadian Academy of Pathology
  • Int'l Joint Research
• [Presentation] A combination of MTAP and BAP1 immunohistochemistry is useful for differentiating malignant and benign mesothelial proliferatons in tissue and cytological specimens. (2017)
  • Author(s): Yoshiaki Kinoshita, Tomoyuki Hida, Makoto Hamasaki, Shinji Matsumoto, Tohru Tsujimura, Kunimitsu Kawahara, Kenzo Hiroshima, Yoshinao Oda, and Kazuki Nabeshima.
  • Organizer: 106th Annual Meeting of United States & Canadian Academy of Pathology
  • Int'l Joint Research
• [Presentation] An autopsy case of sarcomatoid mesothelioma. (2017)
  • Author(s): Yohei Ogawa, Mikiko Aoki, Yasuhito Mihashi, Makoto Hamasaki, Tomoya Sasaki, Kentaro Watanabe, Morishige Takeshita, Kazuki Nabeshima.
  • Organizer: 第106回日本病理学会総会
• [Presentation] The effects of formalin fixing conditions on fluorescence in situ hybridization in cell block of effusion cytology. (2017)
  • Author(s): Shinji Matsumoto, Yuko Ouchi, Katsumi Kobata, Makoto Hamasaki, Kazuki Nabeshima.
  • Organizer: 第58回日本臨床細胞学会
• [Presentation] Analysis of p16 deletion and loss of BAP1 in peritoneal mesotheliomas in Japan and in China. (2017)
  • Author(s): Kenzo Hiroshima, Di Wu, Zhibin Gao, Kazuki Nabeshima, Tohru Tsujimura.
  • Organizer: 2017 Pulmonary Pathology Society 10th Biennial Meeting.
  • Int'l Joint Research
• [Presentation] 悪性胸膜中皮腫と良性中皮過形成の鑑別におけるMTAPIHC及びBAP1IHCの有用性. (2017)
  • Author(s): 木下 義晃、樋田 知之、濱崎慎、松本慎二、辻村亨, 佐藤鮎子, 河原邦光, 廣島健三, 小田義直, 鍋島一樹.
  • Organizer: 第58回日本肺癌学会学術集会
• [Presentation] 中皮腫の早期診断に役立つp16 FISHとBAP1, MTAP免疫染色. (2017)
  • Author(s): 鍋島一樹、木下義晃、松本慎二、樋田知之,佐藤鮎子, 辻村亨, 河原邦光, 廣島健三, 亀井敏昭, 小田義直.
  • Organizer: 第58回日本臨床細胞学会総会 シンポジウム３.
• [Presentation] 中皮腫の組織/細胞診診断 update-遺伝子変異に基づく免疫染色・FISHの応用. (2017)
  • Author(s): 鍋島一樹.
  • Organizer: 第34回日本呼吸器外科学会総会 教育講演
• [Presentation] 中皮腫の細胞診update. (2017)
  • Author(s): 鍋島一樹、木下義晃、松本慎二、樋田知之, 佐藤鮎子, 辻村亨, 河原邦光, 廣島健三, 亀井敏昭, 小田義直.
  • Organizer: 第106回日本病理学会総会コンパニオンミーティング 中皮腫診断の最前線
• [Presentation] 中皮腫の遺伝子変異と診断への応用. (2017)
  • Author(s): 鍋島一樹.
  • Organizer: 第11回九州肺癌胸膜中皮腫研究会・特別講演.
• [Presentation] BAP1 immunostaining and p16 FISH results in combination provide higher confidence in malignant pleural mesothelioma diagnosis. (2016)
  • Author(s): Nabeshima K, Hida T, Matsumoto S, Hamasaki M, Sato A, Tsujimura T, Kawahara K, Kamei T, Iwasaki A, Oda Y.
  • Organizer: The 19th International Congress of Cytology
  • Place of Presentation: Yokohama, Japan
  • Year and Date: 2016-05-28
  • Int'l Joint Research / Invited
• [Presentation] Immunohistochemical detection of MTAP or BAP1 protein loss for mesothelioma diagnosis: Comparison with p16 FISH. (2016)
  • Author(s): Kazuki Nabeshima, Tomoyuki Hida, Makoto Hamasaki, Shinji Matsumoto, Ayuko Sato, Tohru Tsujimura, Kunimitsu Kawahara, Akinori Iwasaki, Yoshinao Od.
  • Organizer: 13th International Conference of the International Mesothelioma Interest Group
  • Place of Presentation: Birmingham, UK
  • Year and Date: 2016-05-01
  • Int'l Joint Research / Invited
• [Book] 悪性胸膜中皮腫細胞診断の手引き. (2017)
  • Author(s): 日本肺癌学会細胞診判定基準改訂委員会・中皮腫細胞診評価ワーキンググループ：佐藤之俊，廣島健三，木浦勝行，薄田勝男，大林千穂，河原邦光，桜田晃，羽場礼次，三浦弘之，三窪将史，吉澤明彦, 柿沼廣邦，竹中明美，三宅真司, 亀井敏昭，秋田弘俊，岡輝明，河合俊明，児玉哲郎，武島幸男，辻村亨，鍋島一樹，畠榮，他.
  • Publisher: 日本肺癌学会
• [Book] 平成28年度石綿関連疾患に係る医学的所見の解析調査業務（FISH法等を用いた中皮腫診断法の開発に関する調査編）報告書 (2017)
  • Author(s): 吉村雅代、鍋島一樹、木下義晃、松本慎二、濵﨑慎、樋田知之.
  • Total Pages: 63
  • Publisher: 環境省
• [Book] 平成28年度石綿関連疾患に係る医学的所見の解析調査業務（FISH法等を用いた中皮腫診断法の開発に関する調査編）報告書 (2017)
  • Author(s): 鍋島一樹、木下義晃、樋田知之、松本慎二、濵﨑慎、佐藤鮎子、辻村亨、廣島健三.
  • Total Pages: 63
  • Publisher: 環境省